Quinazoline derivatives as medicaments

ABSTRACT

The invention is directed to methods to inhibit TGF-β and/or p38-α kinase using compounds of the formula                    
     or the pharmaceutically acceptable salts thereof 
     wherein R 3  is a noninterfering substituent; 
     each Z is CR 2  or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N; 
     each R 2  is independently a noninterfering substituent; 
     L is a linker; 
     n is 0 or 1; and 
     Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

This application is a divisional of application Ser. No. 09/383,825,filed Aug. 27, 1999, which is a continuation-in-part of Ser. No.09/141,916, now U.S. Pat. No. 6,184,226, filed Aug. 28, 1998.

FIELD OF THE INVENTION

The invention relates to treating various disorders associated withenhanced activity of kinase p38-α and/or transforming growth factor beta(TGF-β). More specifically, it concerns compounds that are related toquinazoline as useful in these methods.

BACKGROUND ART

A large number of chronic and acute conditions have been recognized tobe associated with perturbation of the inflammatory response. A largenumber of cytokines participate in this response, including IL-1, IL-6,IL-8 and TNF. It appears that the activity of these cytokines in theregulation of inflammation rely at least in part on the activation of anenzyme on the cell signaling pathway, a member of the MAP kinase familygenerally known as p38 and alternatively known as CSBP and RK. Thiskinase is activated by dual phosphorylation after stimulation byphysiochemical stress, treatment with lipopolysaccharides or withproinflammatory cytokines such as IL-1 and TNF. Therefore, inhibitors ofthe kinase activity of p38 are useful antiinflammatory agents.

Transforming growth factor-beta (TGF-β) denotes a family of proteins,TGF-β1, TGF-β2, and TGF-β3, which are pleiotropic modulators of cellgrowth and differentiation, embryonic and bone development,extracellular matrix formation, hematopoiesis, immune and inflammatoryresponses (Roberts and Sporn Handbook of Experimental Pharmacology(1990) 95:419-58; Massague et al. Ann Rev Cell Biol (1990) 6:597-646).Other members of this superfamily include activin, inhibin, bonemorphogenic protein, and Mullerian inhibiting substance. TGF-β initiatesan intracellular signaling pathway leading ultimately to the expressionof genes that regulate the cell cycle, control proliferative responses,or relate to extracellular matrix proteins that mediate outside-in cellsignaling, cell adhesion, migration and intercellular communication.

Therefore, inhibitors of the TGF-β intracellular signaling pathway areuseful treatments for fibroproliferative diseases. Specifically,fibroproliferative diseases include kidney disorders associated withunregulated TGF-β activity and excessive fibrosis includingglomerulonephritis (GN), such as mesangial proliferative GN, immune GN,and crescentic GN. Other renal conditions include diabetic nephropathy,renal interstitial fibrosis, renal fibrosis in transplant patientsreceiving cyclosporin, and HIV-associated nephropathy. Collagen vasculardisorders include progressive systemic sclerosis, polymyositis,scleroderna, dermnatomyositis, eosinophilic fascitis, morphea, or thoseassociated with the occurrence of Raynaud's syndrome. Lung fibrosesresulting from excessive TGF-β activity include adult respiratorydistress syndrome, idiopathic pulmonary fibrosis, and interstitialpulmonary fibrosis often associated with autoimmune disorders, such assystemic lupus erythematosus and scleroderma, chemical contact, orallergies. Another autoimmune disorder associated withfibroproliferative characteristics is rheumatoid arthritis.

Eye diseases associated with a fibroproliferative condition includeretinal reattachment surgery accompanying proliferativevitreoretinopathy, cataract extraction with intraocular lensimplantation, and post glaucoma drainage surgery.

PCT applications WO98/06715, WO98/07425, and WO 96/40143, all of whichare incorporated herein by reference, describe the relationship of p38kinase inhibitors with various disease states. As mentioned in theseapplications, inhibitors of p38 kinase are useful in treating a varietyof diseases associated with chronic inflammation. These applicationslist rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions, sepsis, septic shock,endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma,adult respiratory distress syndrome, stroke, reperfusion injury, CNSinjuries such as neural trauma and ischemia, psoriasis, restenosis,cerebral malaria, chronic pulmonary inflammatory disease, silicosis,pulmonary sarcosis, bone resorption diseases such as osteoporosis,graft-versus-host reaction, Crohn's Disease, ulcerative colitisincluding inflammatory bowel disease (IBD) and pyresis.

The above-referenced PCT applications disclose compounds which are p38kinase inhibitors said to be useful in treating these disease states.These compounds are either imidazoles or are indoles substituted at the3- or 4-position with a piperazine ring linked through a carboxamidelinkage. Additional compounds which are conjugates of piperazines withindoles are described as insecticides in WO97/26252, also incorporatedherein by reference.

The compounds of the invention are quinazoline derivatives. Otherquinazoline compounds for other uses have been described. U.S. Pat. No.5,721,237 assigned to Rhone-Poulenc Rorer is directed to methods forselective treatment of cell growth and differentiation characterized byactivity of human epidermal growth factor receptor type II usingquinazoline substituted only in the 4-position with an aromatic moietyoptionally coupled to the quinazoline through a linking moiety. U.S.Pat. No. 4,480,883 describes compounds that exhibit tyrosine kinaseinhibition activity wherein the heterocyclic portion of a quinazoline orother fused ring nitrogen-containing aromatic system is substituted onlyonce with an aromatic moiety, again optionally coupled through a linker.U.S. Pat. No. 5,616,582 assigned to Zeneca describes tyrosine kinaseinhibitors which are quinazolines linked through an amino group at the4-position to a substituted or unsubstituted phenyl. These compoundscontain no substituents at position 2. U.S. Pat. No. 5,475,001 alsoassigned to Zeneca describes similar compounds with the same activity.U.S. Pat. No. 5,430,148 assigned to Agouron Pharmaceutical describesantiproliferative substituted quinazolinones and their counterpartswherein the keto group is replaced by a sulfone.

U.S. Pat. No. 5,719,157 to Takeda Chemical Industries describespharmaceutical compositions for inhibiting bone resorption which include4-phenyl quinoline derivatives which may further be substituted at the2-position with an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group.

None of the foregoing patents describes quinazoline derivatives whichspecifically inhibit p38-α or TGF-β.

DISCLOSURE OF THE INVENTION

The invention is directed to methods and compounds useful in treatingconditions that are characterized by enhanced p38-α activity and/orTGF-β activity. These conditions include inflammation, proliferativediseases, and certain cardiovascular disorders as further describedbelow.

Compounds of the invention have been found to inhibit p38 kinase, theα-isoform in particular, and/or TGF-β and are thus useful in treatingdiseases mediated by these activities. The compounds of the inventionare of the formula

or the pharmaceutically acceptable salts thereof

wherein R³ is a noninterfering substituent;

each Z is CR² or N, wherein no more than two Z positions in ring A areN, and wherein two adjacent Z positions in ring A cannot be N;

each R² is independently a noninterfering substituent;

L is a linker;

n is 0 or 1; and

Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic,aromatic or heteroaromatic moiety optionally substituted with 1-3noninterfering substituents.

The invention is directed to methods of treating inflammation orproliferative conditions using these compounds. The invention is alsodirected to treating conditions associated with cardiac failure usingthe invention compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C show the structures of compounds prepared according to themethods of the invention and useful in the invention methods.

MODES OF CARRYING OUT THE INVENTION

The compounds of formula (1) are useful in treating conditions which arecharacterized by overactivity of p38 kinase, in particular the α-isoformand/or overactivity of TGF-β. Conditions “characterized by enhancedp38-α activity” include those where this enzyme is present in increasedamount or wherein the enzyme has been modified to increase its inherentactivity, or both. Conditions “characterized by enhanced TGF-β activity”include those wherein TGF-β synthesis is stimulated so that TGF-β ispresent in enhanced amount or wherein TGF-β latent protein isundesirably activated or converted to active TGF-β protein or whereinTGF-β receptors are upregulated or wherein the TGF-β protein showsenhanced binding to cells or extracellular matrix in the location of thedisease. Thus, in either case, “enhanced activity” refers to anycondition wherein the effectiveness of either of these proteins isundesirably high, regardless of the cause.

The compounds of the invention are useful in conditions where eitherp38-α kinase or TGF-β shows enhanced activity since these compoundsinhibit the activities of both proteins. This is particularlyadvantageous in conditions which are characterized by enhancedactivities of both proteins. These conditions are those in whichfibrosis and organ sclerosis are caused by, or accompanied by,inflammation, oxidation injury, hypoxia, altered temperature orextracellular osmolarity, conditions causing cellular stress, apoptosisor necrosis. These conditions include ischemia-reperfusion injury,congestive heart failure, progressive pulmonary and bronchial fibrosis,hepatitis, arthritis, inflammatory bowel disease, glomerular sclerosis,interstitial renal fibrosis, chronic scarring diseases of the eyes,bladder and reproductive tract, bone marrow dysplasia, chronicinfectious or autoimmune states and traumatic or surgical wounds. Theseconditions, of course, would be benefited by compounds which inhibiteither TGF-β or p38-α. They are especially benefited by treatment withcompounds that inhibit both. Methods of treatment with the compounds ofthe invention are further discussed below.

The Invention Compounds

The compounds useful in the invention are derivatives of quinazoline andrelated compounds containing mandatory substituents at positionscorresponding to the 2- and 4-positions of quinazoline. In general, aquinazoline nucleus is preferred, although alternatives within the scopeof the invention are also illustrated below. Preferred embodiments forZ³ are N and CH; preferred embodiments for Z⁵-Z⁸ are CR². However, eachof Z⁵-Z⁸ can also be N, with the proviso noted above. Thus, with respectto the basic quinazoline type ring system, preferred embodiments includequinazoline per se, and embodiments wherein all of Z⁵-Z⁸ as well as Z³are either N or CH. Also preferred are those embodiments wherein Z³ isN, and either Z⁵ or Z⁸ or both Z⁵ and Z⁸ are N and Z⁶ and Z⁷ are CH orCR². Where R² is other than H, it is preferred that CR² occur atpositions 6 and/or 7.

As used herein, a “noninterfering substituent” is a substituent whichleaves the ability of the compound of formula (1) to inhibit p38-αactivity and/or TGF-β activity qualitatively intact. Thus, thesubstituent may alter the degree of inhibition and the balance betweenp38-α inhibition and TGF-β inhibition. However, as long as the compoundof formula (1) retains the ability to inhibit either p38-α or TGF-βactivity or both, the substituent will be classified as“noninterfering.”

As used herein, “hydrocarbyl residue” refers to a residue which containsonly carbon and hydrogen. The residue may be aliphatic or aromatic,straight-chain, cyclic, branched, saturated or unsaturated. Thehydrocarbyl residue, when indicated, may contain heteroatoms over andabove the carbon and hydrogen members of the substituent residue. Thus,when specifically noted as containing such heteroatoms, the hydrocarbylresidue may also contain carbonyl groups, amino groups, hydroxyl groupsand the like, or contain heteroatoms within the “backbone” of thehydrocarbyl residue.

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” includestraight- and branched-chain and cyclic monovalent substituents.Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl,2-propenyl, 3-butynyl, and the-like. Typically, the alkyl, alkenyl andalkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl oralkynyl). Preferably they contain 1-6C (alkyl) or 2-6C (alkenyl oralkynyl). Heteroalkyl, heteroalkenyl and heteroalkynyl are similarlydefined but may contain 1-2 O, S or N heteroatoms or combinationsthereof within the backbone residue.

As used herein, “acyl” encompasses the definitions of alkyl, alkenyl,alkynyl and the related hetero-forms which are coupled to an additionalresidue through a carbonyl group.

“Aromatic” moiety refers to a monocyclic or fused bicyclic moiety suchas phenyl or naphthyl; “heteroaromatic” also refers to monocyclic orfused bicyclic ring systems containing one ore more heteroatoms selectedfrom O, S and N. The inclusion of a heteroatom permits inclusion of5-membered rings as well as 6-membered rings. Thus, typical aromaticsystems include pyridyl, pyrimidyl, indolyl, benzimidazolyl,benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl,thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like.Any monocyclic or fused ring bicyclic system which has thecharacteristics of aromaticity in terms of electron distributionthroughout the ring system is included in this definition. Typically,the ring systems contain 5-12 ring member atoms.

Similarly, “arylalkyl” and “heteroalkyl” refer to aromatic andheteroaromatic systems which are coupled to another residue through acarbon chain, including substituted or unsubstituted, saturated orunsaturated, carbon chains, typically of 1-6C. These carbon chains mayalso include a carbonyl group, thus making them able to providesubstituents as an acyl moiety.

With respect to the substituent at the positions corresponding to the4-position of quinazoline, LAr′, L is present or absent and is a linkerwhich spaces the substituent Ar′ from ring B at a distance of 2-8 Å,preferably 2-6 Å, more preferably 2-4 Å. The distance is measured fromthe ring carbon in ring B to which one valence of L is attached to theatom of the Ar′ cyclic moiety to which the other valence of the linkeris attached. The Ar′ moiety may also be coupled directly to ring B(i.e., when n is 0). Typical, but nonlimiting, embodiments of L are ofthe formula S(CR² ₂)_(m), —NR¹SO₂(CR² ₂)₁, NR¹(CR² ₂)_(m), NR¹CO(CR²₂)₁, O(CR² ₂)_(m), OCO(CR² ₂)₁, and

wherein Z is N or CH and wherein m is 0-4 and l is 0-3, preferably 1-3and 1-2, respectively. L preferably provides —NR¹— coupled directly toring B. A preferred embodiment of R¹ is H, but R¹ may also be acyl,alkyl, arylacyl or arylalkyl where the aryl moiety may be substituted by1-3 groups such as alkyl, alkenyl, alkynyl, acyl, aryl, alkylaryl,aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR, —SOR, —NRSOR,—NRSO₂R, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, —RCO, —COOR,—SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independentlyH or alkyl (1-4C), preferably the substituents are alkyl (1-6C), OR, SRor NR₂ wherein R is H or lower alkyl (1-4C). More preferably, R¹ is H oralkyl (1-6C). Any aryl groups contained in the substituents may furtherbe substituted by for example alkyl, alkenyl, alkynyl, halo, OR, NR₂,SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, —RCO, —COOR,SO₂R, NRSOR, NRSO₂R, —SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, or NO₂, whereineach R is independently H or alkyl (1-4C).

Ar′ is aryl, heteroaryl, including 6-5 fused heteroaryl, cycloaliphaticor cycloheteroaliphatic. Preferably Ar′ is phenyl, 2-, 3- or 4-pyridyl,indolyl, 2- or 4-pyrimidyl, benzimidazolyl, indolyl, preferably eachoptionally substituted with a group selected from the group consistingof optionally substituted alkyl, alkenyl, alkynyl, aryl, N-aryl,NH-aroyl, halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, SO₂NR₂,CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C).

Ar′ is more preferably indolyl, 6-pyrimidyl, 3- or 4-pyridyl, oroptionally substituted phenyl.

For embodiments wherein Ar′ is optionally substituted phenyl,substituents include, without limitation, alkyl, alkenyl, alkynyl, aryl,alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂, SR,—SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, RCO, —COOR,—SO₃R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independentlyH or alkyl (1-4C). Preferred substituents include halo, OR, SR, and NR₂wherein R is H or methyl or ethyl. These substituents may occupy allfive positions of the phenyl ring, preferably 1-2 positions, preferablyone position. Embodiments of Ar′ include substituted or unsubstitutedphenyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 6-pyrimidyl, indolyl,isoquinolyl, quinolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl,benzofuranyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,imidazolyl, and morpholinyl. Particularly preferred as an embodiment ofAr′ is 3- or 4-pyridyl, especially 4-pyridyl in unsubstituted form.

Any of the aryl moieties, especially the phenyl moieties, may alsocomprise two substituents which, when taken together, form a 5-7membered carbocyclic or heterocyclic aliphatic ring.

Thus, preferred embodiments of the substituents at the position of ringB corresponding to 4-position of the quinazoline include2-(4-pyridyl)ethylamino; 4-pyridylamino; 3-pyridylamino; 2-pyridylamino;4-indolylamino; 5-indolylamino; 3-methoxyanilinyl;2-(2,5-difluorophenyl)ethylamino-, and the like.

R³ is generally a hydrocarbyl residue (1-20C) containing 0-5 heteroatomsselected from O, S and N. Preferably R³ is alkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, or heteroarylalkyl, each unsubstituted orsubstituted with 1-3 substituents. The substituents are independentlyselected from a group that includes halo, OR, NR₂, SR, —SOR, —SO₂R,—OCOR, —NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, RCO, —COOR, —SO₃R, NRSOR,NRSO₂R, —CONR₂, SO₂NR₂, CN, CF₃, and NO₂, wherein each R isindependently H or alkyl (1-4C) and with respect to any aryl orheteroaryl moiety, said group further including alkyl (1-6C) or alkenylor alkynyl. Preferred embodiments of R³ (the substituent at positioncorresponding to the 2-position of the quinazoline) comprise a phenylmoiety optionally substituted with 1-2 substituents preferably halo,alkyl (1-6C), OR, NR₂, and SR wherein R is as defined above. Thus,preferred substituents at the 2-position of the quinazoline includephenyl, 2-bromophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl,4-fluorophenyl and the like. Other preferred embodiments of R³ comprisea cyclopentyl or cyclohexyl moiety.

As noted above, R² is a noninterfering substituent. As set forth above,a “noninterfering substituent” is one whose presence does notsubstantially destroy the p38-α kinase inhibiting ability and/or TGF-βinhibiting ability of the compound of formula (1).

Each R² is also independently a hydrocarbyl residue (1-20C) containing0-5 heteroatoms selected from O, S and N. Preferably, R² isindependently H, alkyl, alkenyl, alkynyl, acyl or hetero-forms thereofor is aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, eachunsubstituted or substituted with 1-3 substituents selectedindependently from the group consisting of alkyl, alkenyl, alkynyl,aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR₂,SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, NRSOR, NRSO₂R,—OCONR₂, RCO, —COOR, —SO₃R, NRSOR, NRSO₂R, —CONR₂, SO₂NR₂, CN, CF₃, andNO₂, wherein each R is independently H or alkyl (1-4C). The aryl oraroyl groups on said substituents may be further substituted by, forexample, alkyl, alkenyl, alkynyl, halo, OR, NR₂, SR, —SOR, —SO₂R, —OCOR,—NRCOR, —NRCONR₂, —NRCOOR, —OCONR₂, RCO, —COOR, —SO₃R, —CONR₂, SO₂NR₂,CN, CF₃, and NO₂, wherein each R is independently H or alkyl (1-4C).More preferably the substituents on R² are selected from R⁴, halo, OR⁴,NR⁴ ₂, SR⁴, —OCOR⁴, —NRCOR⁴, —COOR⁴, R⁴CO, —CONR⁴ ₂, —SO²NR⁴ ₂, CN, CF₃,and NO₂, wherein each R⁴ is independently H, or optionally substitutedalkyl (1-6C), or optionally substituted arylalkyl (7-12C) and whereintwo R⁴ or two substituents on said alkyl or arylalkyl taken together mayform a fused aliphatic ring of 5-7 members.

R₂ may also, itself, be selected from the group consisting of halo, OR,NR₂, SR, —SOR, —SO₂R, —OCOR, —NRCOR, —NRCONR₂, —NRCOOR, NRSOR, NRSO₂R,—OCONR₂, RCO, —COOR, —SO₃R, NRSOR, NRSO₂R, —CONR₂, SO₂NR₂, CN, CF₃, andNO₂, wherein each R is independently H or alkyl (1-4C).

More preferred substituents represented by R² are those as set forthwith regard to the phenyl moieties contained in Ar′ or R³ as set forthabove. Two adjacent CR² taken together may form a carbocyclic orheterocyclic fused aliphatic ring of 5-7 atoms. Preferred R²substituents are of the formula R⁴, —OR⁴, SR⁴ or R⁴NH—, especiallyR⁴NH—, wherein R⁴ is defined as above. Particularly preferred areinstances wherein R⁴ is substituted arylalkyl.

The compounds of formula (1) may be supplied in the form of theirpharmaceutically acceptable acid-addition salts including salts ofinorganic acids such as hydrochloric, sulfuric, hydrobromic, orphosphoric acid or salts of organic acids such as acetic, tartaric,succinic, benzoic, salicylic, and the like. If a carboxyl moiety ispresent on the compound of formula (1), the compound may also besupplied as a salt with a pharmaceutically acceptable cation.

Synthesis of the Invention Compounds

The compounds of the invention may be synthesized from the corresponding4-halo-2-phenyl quinazoline as described in Reaction Scheme 1; which maybe obtained from the corresponding 4-hydroxyquinazoline as shown inReaction Scheme 2. Alternatively, the compounds can be prepared usinganthranylamide as a starting material and benzoylating the amino groupfollowed by cyclization to obtain the intermediate 2-phenyl-4-hydroxyquinazoline as shown in Reaction Scheme 3. Reaction Schemes 4-6 aresimilar to Reaction Scheme 3 except that an appropriate pyridine or1,4-pyrimidine nucleus, substituted with a carboxamide residue and anadjacent amino residue, is substituted for the anthranylimide. Thecompounds of the invention wherein R¹ is H can be further derivatized tocomprise other embodiments of R¹ as shown in Reaction Scheme 7.

Reaction Scheme 1 is illustrative of the simple conversion of ahalogenated quinazoline to compounds of the invention. Of course, thephenyl of the illustration at position 2 may be generalized as R³ andthe 4-pyridylamino at position 2 can be generalized to Ar′—L or Ar′—.

Reaction Scheme 2 can, of course, be generalized in the same manner asset forth for Reaction Scheme 1.

Again, Reaction Scheme 3 can be generalized by substituting thecorresponding acyl halide, R³COCl for the parafluorobenzoyl chloride.Further, Ar′ or Ar′—L may be substituted for 4-aminopyridine in the laststep.

Reaction Scheme 5

Reaction Scheme 6

It is seen that Reaction Scheme 1 represents the last step of ReactionSchemes 2-6 and that Reaction Scheme 2 represents the last two steps ofReaction Scheme 3-6.

Reaction Scheme 7 provides conditions wherein compounds of formula (1)are obtained wherein R¹ is other than H.

Reaction Scheme 8 is a modification of Reaction Scheme 3 which simplydemonstrates that substituents on ring A are carried through thesynthesis process. The principles of the behavior of the substituentsapply as well to Reactions Schemes 4-6.

Reaction Scheme 8 shows a modified form of Reaction Scheme 3 whichincludes substituents R² in the quinazoline ring of formula (1). Thesubstituents are carried throughout the reaction scheme. In step a, thestarting material is treated with thionyl chloride in the presence ofmethanol and refluxed for 12 hours. In step b, the appropriatesubstituted benzoyl chloride is reacted with the product of step a bytreating with the appropriately substituted benzoyl chloride in pyridinefor 24 hours. In embodiments wherein X (shown illustratively in theortho-position) is fluoro, 2-fluorobenzoyl chloride is used as areagent; where X is (for illustration ortho-chloro), 2-chlorobenzoylchloride is used.

In step c, the ester is converted to the amide by treating in ammoniumhydroxide in an aprotic solvent such as dimethyl formamide (DMF) for 24hours. The product is then cyclized in step d by treatment with 10 NNaOH in ethanol and refluxed for 3 hours.

The resulting cyclized form is then converted to the chloride in step eby treating with thionyl chloride in chloroform in the presence of acatalytic amount of DMF under reflux for 4 hours. Finally, theillustrated 4-pyridylamino compound is obtained in step f by treatingwith 4-amino pyridine in the presence of potassium carbonate and DMF andrefluxed for 2 hours.

In illustrative embodiments of Reaction Scheme 8, R² may, for example,provide two methoxy substituents so that the starting material is2-amino-4,5-dimethoxy benzoic acid and the product is, for example,2-(2-chlorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline.

In another illustrative embodiment, R² provides a single nitro; thestarting material is thus, for example, 2-amino-5-nitrobenzoic acid andthe resulting compound is, for example,2(2-fluorophenyl)-4-(4-pyridylamino)-5-nitroquinazoline.

Reaction Schemes 4-6 can be carried out in a manner similar to that setforth in Reaction Scheme 8, thus carrying along R² substituents throughthe steps of the process.

In compounds of the invention wherein R² is nitro, the nitro group maybe reduced to amino and further derivatized as indicated in ReactionScheme 9.

In Reaction Scheme 9, the illustrative product of Reaction Scheme 8 isfirst reduced in step g by treating with hydrogen and palladium oncarbon (10%) in the presence of acetic acid and methanol at atmosphericpressure for 12 hours to obtain the amino compound. The resulting aminocompound is either converted to the acyl form (R=acyl) using theappropriate acid chloride in the presence of chloroform and pyridine forfour hours, or is converted to the corresponding alkylated amine(R=alkyl) by treating the amine intermediate with the appropriatealdehyde in the presence of ethanol, acetic acid, and sodiumtriacetoxyborohydride for 4 hours.

While the foregoing exemplary Reaction Schemes are set forth toillustrate the synthetic methods of the invention, it is understood thatthe substituents shown on the quinazoline ring of the products aregenerically of the formula (1) as described herein and that thereactants may be substituted accordingly. Variations to accommodatevarious substituents which represent embodiments of R³ other than themoieties shown in these illustrative examples or as Ar′ in theseillustrative examples may also be used. Similarly, embodiments whereinthe substituent at position 4 contains an arylalkyl can be used in theseschemes. Methods to synthesize the compounds of the invention are, ingeneral, known in the art.

Administration and Use

The compounds of the invention are useful among other indications intreating conditions associated with inflammation. Thus, the compounds offormula (1) or their pharmaceutically acceptable salts are used in themanufacture of a medicament for prophylactic or therapeutic treatment ofmammals, including humans, in respect of conditions characterized byexcessive production of cytokines and/or inappropriate or unregulatedcytokine activity on such cells as cardiomyocytes, cardiofibroblasts andmacrophages.

The compounds of the invention inhibit the production of cytokines suchas TNF, IL-1, IL-6 and IL-8, cytokines that are importantproinflammatory constituents in many different disease states andsyndromes. Thus, inhibition of these cytokines has benefit incontrolling and mitigating many diseases. The compounds of the inventionare shown herein to inhibit a member of the MAP kinase family variouslycalled p38 MAPK (or p38), CSBP, or SAPK-2. The activation of thisprotein has been shown to accompany exacerbation of the diseases inresponse to stress caused, for example, by treatment withlipopolysaccharides or cytokines such as TNF and IL-1. Inhibition of p38activity, therefore, is predictive of the ability of a medicament toprovide a beneficial effect in treating diseases such as coronary arterydisease, congestive heart failure, cardiomyopathy, myocarditis,vasculitis, restenosis, such as occurs following coronary angioplasty,atherosclerosis, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, multiplesclerosis, acute respiratory distress syndrome (ARDS), asthma, chronicobstructive pulmonary disease (COPD), silicosis, pulmonary sarcosis,sepsis, septic shock, endotoxic shock, toxic shock syndrome, heart andbrain failure (stroke) that are characterized by ischemia andreperfusion injury, surgical procedures, such as transplantationprocedures and graft rejections, cardiopulmonary bypass, coronary arterybypass graft, CNS injuries, including open and closed head trauma,inflammatory eye conditions such as conjunctivitis and uveitis, acuterenal failure, glomerulonephritis, inflammatory bowel diseases, such asCrohn's disease or ulcerative colitis, graft vs host disease, boneresorption diseases like osteoporosis, type II diabetes, pyresis,psoriasis, cachexia, viral diseases such as those caused by HIV, CMV,and Herpes, and cerebral malaria.

Within the last several years, p38 has been shown to comprise a group ofMAP kinases designated p38-α, p38-β, p38-γ and p38-δ. Jiang, Y. et al. JBiol Chem (1996) 271:17920-17926 reported characterization of p38-β as a372-amino acid protein closely related to p38-α. In comparing theactivity of p38-α with that of p38-β, the authors state that while bothare activated by proinflammatory cytokines and environmental stress,p38-β was preferentially activated by MAP kinase kinase-6 (MKK6) andpreferentially activated transcription factor 2, thus suggesting thatseparate mechanisms for action may be associated with these forms.

Kumar, S. et al. Biochem Biophys Res Comm (1997) 235:533-538 and Stein,B. et al. J Biol Chem (1997) 272:19509-19517 reported a second isoformof p38-β, p38-β2, containing 364 amino acids with 73% identity to p38-α.All of these reports show evidence that p38-β is activated byproinflammatory cytokines and environmental stress, although the secondreported p38-β isoform, p38-β2, appears to be preferentially expressedin the CNS, heart and skeletal muscle compared to the more ubiquitoustissue expression of p38-α. Furthermore, activated transcriptionfactor-2 (ATF-2) was observed to be a better substrate for p38-β2 thanfor p38-α, thus suggesting that separate mechanisms of action may beassociated with these forms. The physiological role of p38-β1 has beencalled into question by the latter two reports since it cannot be foundin human tissue and does not exhibit appreciable kinase activity withthe substrates of p38-α.

The identification of p38-γ was reported by Li, Z. et al. BiochemBiophys Res Comm (1996) 228:334-340 and of p38-δ by Wang, X., et al., JBiol Chem (1997) 272:23668-23674 and by-Kumar, S., et al., BiochemBiophys Res Comm (1997) 235:533-538. The data suggest that these two p38isoforms (γ and δ) represent a unique subset of the MAPK family based ontheir tissue expression patterns, substrate utilization, response todirect and indirect stimuli, and susceptibility to kinase inhibitors.

Various results with regard to response to drugs targeting the p38family as between p38-α and either the putative p38-β1 or p38-β2 or bothwere reported by Jiang, Kumar, and Stein cited above as well as byEyers, P. A. et al. Chem and Biol (1995) 5:321-328. An additional paperby Wang, Y. et al. J Biol Chem (1998) 273:2161-2168 suggests thesignificance of such differential effects. As pointed out by Wang, anumber of stimuli, such as myocardial infarction, hypertension, valvulardiseases, viral myocarditis, and dilated cardiomyopathy lead to anincrease in cardiac workload and elevated mechanical stress oncardiomyocytes. These are said to lead to an adaptive hypertrophicresponse which, if not controlled, has decidedly negative consequences.Wang cites previous studies which have shown that in ischemiareperfusion treated hearts, p38 MAPK activities are elevated inassociation with hypertrophy and programmed cell death. Wang shows inthe cited paper that activation of p38-β activity results inhypertrophy, whereas activation of p38-α activity leads to myocyteapoptosis. Thus, selective inhibition of p38-α activity as compared top38-β activity will be of benefit in treating conditions associated withcardiac failure. These conditions include congestive heart failure,cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valvulardisease, conditions associated with cardiopulmonary bypass, coronaryartery bypass, grafts and vascular grafts. Further, to the extent thatthe α-isoform is toxic in other muscle cell types, α-selectiveinhibitors would be useful for conditions associated with cachexiaattributed to TNF or other conditions such as cancer, infection, orautoimmune disease.

Thus, the invention encompasses the use of compounds which selectivelyinhibit the activity of the p38-α isoform for treating conditionsassociated with activation of p38-α, in particular those associated withcardiac hypertrophy, ischemia or other environmental stress such asoxidation injury, hyperosmolarity or other agents or factors thatactivate p38-α kinase, or cardiac failure, for example, congestive heartfailure, cardiomyopathy and myocarditis.

The TGF-β inhibition activity is useful in treating fibroproliferativediseases, treating collagen vascular disorders, treating eye diseasesassociated with a fibroproliferative condition, venting excessivescarring, treating neurological conditions and other conditions that aretargets for TGF-β inhibitors and in preventing excessive scarring thatelicits and accompanies restenosis following coronary angioplasty,cardiac fibrosis occurring after infarction and progressive heartfailure, and in hypertensive vasculopathy, and keloid formation orhypertrophic scars occurring during the healing of wounds includingsurgical wounds and traumatic lacerations.

Neurological conditions characterized by TGF-β production include CNSinjury after traumatic and hypoxic insults, Alzheimer's disease, andParkinson's disease.

Other conditions that are potential clinical targets for TGF-βinhibitors include myelofibrosis, tissue thickening resulting fromradiation treatment, nasal polyposis, polyp surgery, liver cirrhosis,and osteoporosis.

Diseases benefited by TGF-β inhibition include cardiovascular diseasessuch as congestive heart failure, dilated cardiomyopathy, myocarditis,or vascular stenosis associated with atherosclerosis, angioplastytreatment, or surgical incisions or mechanical trauma; kidney diseasesassociated with fibrosis and/or sclerosis, including glomerulonephritisof all etiologies, diabetic nephropathy, and all causes of renalinterstitial fibrosis, including hypertension, complications of drugexposure, such as cyclosporin, HIV-associated nephropathy, transplantnephropathy, chronic ureteral obstruction; hepatic diseases associatedwith excessive scarring and progressive sclerosis, including cirrhosisdue to all etiologies, disorders of the biliary tree, and hepaticdysfunction attributable to infections such as hepatitis virus orparasites; syndromes associated with pulmonary fibrosis withconsequential loss of gas exchange or ability to efficiently move airinto and out of the lungs, including adult respiratory distresssyndrome, idiopathic pulmonary fibrosis, or pulmonary fibrosis due toinfectious or toxic agents such as smoke, chemicals, allergens, orautoimmune disease; all collagen vascular disorders of a chronic orpersistent nature including progressive systemic sclerosis,polymyositis, scleroderma, dermatomyositis, fascists, or Raynaud'ssyndrome, or arthritic conditions such as rheumatoid arthritis; eyediseases associated with fibroproliferative states, includingproliferative vitreoretinopathy of any etiology or fibrosis associatedwith ocular surgery such as retinal reattachment, cataract extraction,or drainage procedures of any kind; excessive or hypertrophic scarformation in the dermis occurring during wound healing resulting fromtrauma or surgical wounds; disorders of the gastrointestinal tractassociated with chronic inflammation, such as Crohn's disease orulcerative colitis or adhesion formation as a result of trauma orsurgical wounds, polyposis or states post polyp surgery; chronicscarring of the peritoneum associated with endometriosis, ovariandisease, peritoneal dialysis, or surgical wounds; neurologicalconditions characterized by TGF-β production or enhanced sensitivity toTGF-β, including states post-traumatic or hypoxic injury, Alzheimer'sdisease, and Parkinson's disease; and diseases of the joints involvingscarring sufficient to impede mobility or produce pain, including statespost-mechanical or surgical trauma, osteoarthritis and rheumatoidarthritis.

The modulation of the immune and inflammation systems by TGF-β (Wahl etal.

Immunol Today (1989) 10:258-61) includes stimulation of leukocyterecruitment, cytokine production, and lymphocyte effector function, andinhibition of T-cell subset proliferation, B-cell proliferation,antibody formation, and monocytic respiratory burst. TGF-β is astimulator for the excess production of extracellular matrix proteins,including fibronectin and collagen. It also inhibits the production ofenzymes that degrade these matrix proteins. The net effect is theaccumulation of fibrous tissue which is the hallmark offibroproliferative diseases.

TGF-β is active as a homodimer, but is synthesized and secreted fromcells as an inactive latent complex of the mature homodimer andproregions, called latency associated protein (LAP). These proteins bindto each other through noncovalent interactions (Lyons and Moses Eur JBiochem (1990) 187:467). LAP is often disulfide-linked to separate geneproducts, called latent TGF-β binding proteins or LTBPs. These latentforms provide stability for the mature cytokine and a means fortargeting it to the extracellular matrix and cell surfaces (Lawrence EurCytokine Network (1996) 7:363-74). Activation of the latent complexoccurs after secretion from cells and is believed to result from theaction of proteases, such as plasmin (Munger et al. Kidney Intl (1997)51:1376-82), on LAP, thrombospondin-1 binding (Crawford et al. Cell(1998) 93:1159-70), and binding to the integrin v6 (Munger et al. Cell(1999) 319-28).

Other than v6 there is a variety of cell surface proteins/receptors thattransduce the signals initiated by binding of the active TGF-β ligand toits receptors. These include types I, II, III, IV, and V. Type IV ispresent only in the pituitary gland while the others are ubiquitous. Thebinding affinities among the three isoforms for the type I and IIreceptors differ such that these two receptors bind TGF-β1 and TGF-β3[?] more tightly than TGF-β2 (Massague Cell (1992) 69:1067-70).

The type IV receptor or endoglin has a similar isoform binding profilein contrast to the type III receptor, betaglycan, which binds equallywell to all three isoforms (Wang et al. Cell (1991) 67:797-805;Lopez-Casillas Cell (1991) 67:785-95). The type V receptor binds toIGFBP-3 and is thought to have an active kinase domain similar to thetype I and II receptors. Cloning of the type I and type II receptorsdemonstrated the existence of cytoplasmic serine/threonine kinasedomains (Wrana et al. Cell (1992) 71:1003-14; Lin et al. Cell (1992)68:775-85; Ibid. 71:1069; Massague Cell (1992) 69:1067-70). Initiationof the TGF-β signaling pathway results from the binding of the TGF-βligand to the extracellular domain of the type II receptor (Massague AnnRev Biochem (1998) 67:753-91). The bound receptor then recruits type Ireceptor into a multimeric membrane complex, whereupon theconstitutively active type II receptor kinase phosphorylates andactivates type I receptor kinase. The function of the type I receptorkinase is to phosphorylate a receptor-associated co-transcriptionfactor, smad-2/3, thereby releasing it into the cytoplasm where it bindsto smad-4. This smad complex translocates into the nucleus, associateswith a DNA-binding cofactor, such as Fast-1, binds to enhancer regionsof specific genes, and activates transcription. The expression of thesegenes leads to the synthesis of cell cycle regulators that controlproliferative responses or extracellular matrix proteins that mediateoutside-in cell signaling, cell adhesion, migration, and intercellularcommunication.

The manner of administration and formulation of the compounds useful inthe invention and their related compounds will depend on the nature ofthe condition, the severity of the condition, the particular subject tobe treated, and the judgement of the practitioner; formulation willdepend on mode of administration. As the compounds of the invention aresmall molecules, they are conveniently administered by oraladministration by compounding them with suitable pharmaceuticalexcipients so as to provide tablets, capsules, syrups, and the like.Suitable formulations for oral administration may also include minorcomponents such as buffers, flavoring agents and the like. Typically,the amount of active ingredient in the formulations will be in the rangeof 5%-95% of the total formulation, but wide variation is permitteddepending on the carrier. Suitable carriers include sucrose, pectin,magnesium stearate, lactose, peanut oil, olive oil, water, and the like.

The compounds useful in the invention may also be administered throughsuppositories or other transmucosal vehicles. Typically, suchformulations will include excipients that facilitate the passage of thecompound through the mucosa such as pharmaceutically acceptabledetergents.

The compounds may also be administered topically, for topical conditionssuch as psoriasis, or in formulation intended to penetrate the skin.These include lotions, creams, ointments and the like which can beformulated by known methods.

The compounds may also be administered by injection, includingintravenous, intramuscular, subcutaneous or intraperitoneal injection.Typical formulations for such use are liquid formulations in isotonicvehicles such as Hank's solution or Ringer's solution.

Alternative formulations include nasal sprays, liposomal formulations,slow-release formulations, and the like, as are known in the art.

Any suitable formulation may be used. A compendium of art-knownformulations is found in Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Company, Easton, Pa. Reference to this manualis routine in the art.

The dosages of the compounds of the invention will depend on a number offactors which will vary from patient to patient. However, it is believedthat generally, the daily oral dosage will utilize 0.001-100 mg/kg totalbody weight, preferably from 0.01-50 mg/kg and more preferably about0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending onthe conditions being treated and the judgment of the practitioner.

It should be noted that the compounds of formula (1) can be administeredas individual active ingredients, or as mixtures of several embodimentsof this formula. In addition, the inhibitors of p38 kinase or TGF-β, anddual inhibitors of p38kinase and TGF-β kinase, can be used as singletherapeutic agents or in combination with other therapeutic agents.Drugs that could be usefully combined with these compounds includenatural or synthetic corticosteroids, particularly prednisone and itsderivatives, monoclonal antibodies targeting cells of the immune system,antibodies or soluble receptors or receptor fusion proteins targetingimmune or non-immune cytokines, and small molecule inhibitors of celldivision, protein synthesis, or mRNA transcription or translation, orinhibitors of immune cell differentiation or activation.

As implicated above, although the compounds of the invention may be usedin humans, they are also available for veterinary use in treating animalsubjects.

The following examples are intended to illustrate but not to limit theinvention.

EXAMPLE 1 Synthesis of 4-(4-pyridylamino)-2-phenyl Quinazoline

This example illustrates Reaction Scheme 1.

A. 4-Chloro-2-phenyl quinazoline, 1 equivalent, was treated with 1equivalent 4-aminopyridine and 1 equivalent potassium carbonate indimethylformamide (DMF), under reflux for 4 hours. The reaction mixturewas cooled to room temperature and concentrated under vacuum to an oil.This crude material was dissolved in ethyl acetate and chromatographedusing hexane:ethyl acetate:methanol 8:2:0.5 to obtain solid product.Electron impact mass spectroscopy (EIMS) gave a molecular ioncorresponding to the calculated molecular weight of the title compound.

B. Using the procedure of paragraph A of the example but substitutingthe starting materials shown in Table 1 below for 4-aminopyridine, thecorresponding quinazolines shown in the table were obtained.

TABLE 1 Substitute for 4-amino pyridine Product obtained 3-aminopyridine 2-phenyl-4-(3-pyridylamino)-quinazoline 2-amino pyridine2-phenyl-4-(2-pyridylamino)-quinazoline 4-aminomethyl2-phenyl-4-(2-(4-pyridyl)methylamino)-quinazoline pyridine 3-aminomethyl2-phenyl-4-(2-(3-pyridyl)methylamino)-quinazoline pyridine 2-aminomethyl2-phenyl-4-(2-(2-pyridyl)methylamino)-quinazoline pyridine

EXAMPLE 2 Synthesis of 4-(4-pyridylamino)-2-(4-chlorophenyl) Quinazoline

This example illustrates Reaction Scheme 2.

A. 4-Chloro-2-(4-chlorophenyl) quinazoline: 4-hydroxy-2-(4-chlorophenyl)quinazoline, 1 equivalent, was suspended in chloroform and treated with12 equivalents of thionyl chloride in the presence of a catalytic amountof dimethyl formamide, under reflux for 4 hours. After removal of thesolvents under reduced pressure, a solid was obtained that was analyzedby thin layer chromatography and EIMS and found to be4-chloro-2-(4-chlorophenyl) quinazoline.

B. 4-(4-pyridylamino)-2-(4-chlorophenyl) quinazoline:4-chloro-2-(4-chlorophenyl) quinazoline, 1 equivalent, was treated with1 equivalent 4-aminopyridine and 1 equivalent potassium carbonate indimethylformamide (DMF), under reflux for 4 hours, as described inExample 1. The reaction mixture was worked up as in Example 1 andproduct confirmed by EIMS.

EXAMPLE 3 Synthesis of 4-(4-pyridylamino)-2-(4-fluorophenyl) Quinazoline

This example illustrates Reaction Scheme 3.

A. 4-Fluorobenzoyl anthranilamide: Anthranilamide, 1 equivalent, wasdissolved in chloroform/pyridine (1:1) and treated with 4-fluorobenzoylchloride, 1.1 equivalent for one hour at room temperature. The reactionwas concentrated under vacuum. The residue was taken up in ethyl acetateand washed with 1 N aqueous sodium carbonate, 10% aqueous hydrochloricacid, saturated sodium chloride solution and dried over anhydrous sodiumsulfate. Concentration of the ethyl acetate layer gave a white solidthat was found to be homogenous by thin layer chromatography (TLC) andconfirmed by EIMS.

B. 4-Hydroxy-2-(4-fluorophenyl) quinazoline: 4-fluorobenzoylanthranilamide, from paragraph A, 1 equivalent, was dissolved in ethanoland to this was added 10 N aqueous sodium hydroxide, 3.0 equivalents,and the resulting solution heated under reflux for 3 hours. The reactionmixture was cooled to room temperature and concentrated under vacuum.The residue was dissolved in an excess of water and acidified withconcentrated hydrochloric acid. A white precipitate forms uponacidification. This precipitate was filtered and washed extensively withwater. The solid was then dried under high vacuum in the presence ofdessicant. The solid was found to be homogenous by TLC and productconfirmed by EIMS.

C. 4-Chloro-2-(4-fluorophenyl) quinazoline: 4-hydroxy-2-(4-fluorophenyl)quinazoline, from paragraph B, 1 equivalent, was suspended in chloroformand treated with 12 equivalents of thionyl chloride in the presence of acatalytic amount of dimethyl formamide, under reflux for 4 hours. Afterremoval of the solvents under reduced pressure a solid was obtained thatwas analyzed by TLC. EIMS confirmed the desired product.

D. 4-(4-pyridylamino)-2-(4-fluorophenyl) quinazoline:4-chloro-2-(4-fluorophenyl) quinazoline from paragraph C was reacted asin Example 1 to obtain the title compound.

EXAMPLE 4 Synthesis of 2-Phenyl-4-(3-methoxyanilinyl) Quinazoline

4-Chloro-2-phenylquinazoline, 2 equivalents, 3-methoxyanilinyl, 2equivalents, and potassium carbonate, 2 equivalents, were dissolved in10 mL isopropanol and refluxed for 2 hours. The precipitated productformed was filtered and washed with water. Recrystallization frommethanol provided the product as a white solid that was found to behomogenous by thin layer chromatography (TLC) and confirmed by EIMS.

EXAMPLE 5 Synthesis of 4-(4-Methoxybenzyl-4pyridylamino)-2-phenyl)Quinazoline

4-(4-pyridylamino)-2-phenyl quinazoline, 1 equivalent, was dissolved inreagent grade acetone, to this was added 5 equivalents of potassiumhydroxide and 1.5 equivalents of 4-methoxybenzyl chloride. The mixturewas refluxed under nitrogen for 4 hours. After cooling to roomtemperature the reaction mixture was concentrated and the residue takenup in ethyl acetate and washed with saturated aqueous sodium chlorideand dried over anhydrous sodium sulfate and concentrated to give an oil.This crude material was dissolved in ethyl acetate and chromatographedas in Example 1. EIMS confirmed the product.

EXAMPLE 6 Prepared Compounds of the Invention

The compounds in Table 2 shown below have been prepared using thereaction schemes and exemplary procedures set forth herein. In thecompounds of Table 2, Z⁵-Z⁸ are CH and Z³ is N; i.e., these are allquinazoline derivatives per se. The table thus lists the embodiments ofL, Ar and R³.

TABLE 2 Compound No. L Ar′ R³  1 NH 4-pyridyl 2-chlorophenyl  2 NH4-pyridyl 2,6-dichlorophenyl  3 NH 4-pyridyl 2-methylphenyl  4 NH4-pyridyl 2-bromophenyl  5 NH 4-pyridyl 2-fluorophenyl  6 NH 4-pyridyl2,6-difluorophenyl  7 NH 4-pyridyl phenyl  8 NH 4-pyridyl 4-fluorophenyl 9 NH 4-pyridyl 4-methoxyphenyl 10 NH 4-pyridyl 3-fluorophenyl  11* N*4-pyridyl phenyl  12^(†) N^(†) 4-pyridyl phenyl 13 NHCH₂ 4-pyridylphenyl 14 NHCH₂ 4-pyridyl 4-chlorophenyl 15 NH 3-pyridyl phenyl 16 NHCH₂2-pyridyl phenyl 17 NHCH₂ 3-pyridyl phenyl 18 NHCH₂ 2-pyridyl phenyl 19NHCH₂CH₂ 2-pyridyl phenyl 20 NH 6-pyrimidinyl phenyl 21 NH 2-pyrimidinylphenyl 22 NH phenyl phenyl 23 NHCH₂ phenyl 3-chlorophenyl 24 NH3-hydroxyphenyl phenyl 25 NH 2-hydroxyphenyl phenyl 26 NH4-hydroxyphenyl phenyl 27 NH 4-indolyl phenyl 28 NH 5-indolyl phenyl 29NH 4-methoxyphenyl phenyl 30 NH 3-methoxyphenyl phenyl 31 NH2-methoxyphenyl phenyl 32 NH 4-(2-hydroxyethyl)phenyl phenyl 33 NH3-cyanophenyl phenyl 34 NHCH₂ 2,5-difluorophenyl phenyl 35 NH4-(2-butyl)phenyl phenyl 36 NHCH₂ 4-dimethylaminophenyl phenyl 37 NH4-pyridyl cyclopentyl 38 NH 2-pyridyl phenyl 39 NHCH₂ 3-pyridyl phenyl40 NH 4-pyrimidyl phenyl  41^(‡) N^(‡) 4-pyridyl phenyl 42 NHp-aminomethylphenyl phenyl 43 NHCH₂ 4-aminophenyl phenyl 44 NH 4-pyridyl3-chlorophenyl 45 NH phenyl 4-pyridyl 46 NH

phenyl 47 NH 4-pyridyl t-butyl 48 NH 2-benzylamino-3-pyridyl phenyl 49NH 2-benzylamino-4-pyridyl phenyl 50 NH 3-benzyloxyphenyl phenyl 51 NH4-pyridyl 3-aminophenyl 52 NH 4-pyridyl 4-pyridyl 53 NH 4-pyridyl2-naphthyl 54

4-pyridyl phenyl 55

phenyl phenyl 56

2-pyridyl phenyl 57 NHCH₂CH₂

phenyl 58 not present

phenyl 59 not present

phenyl 60 NH 4-pyridyl cyclopropyl 61 NH 4-pyridyl 2-trifluoromethylphenyl 62 NH 4-aminophenyl phenyl 63 NH 4-pyridyl cyclohexyl 64 NH3-methoxyphenyl 2-fluorophenyl 65 NH 4-methoxyphenyl 2-fluorophenyl 66NH 4-pyrimidinyl 2-fluorophenyl 67 NH 3-amino-4-pyridyl phenyl 68 NH4-pyridyl 2-benzylaminophenyl 69 NH 2-benzylaminophenyl phenyl 70 NH2-benzylaminophenyl 4-cyanophenyl 71 NH 3′-cyano-2-benzylaminophenylphenyl *R¹ = 2-propyl ^(†)R¹ = 4-methoxyphenyl ^(‡)R¹ = 4-methoxybenzyl

Compounds 1-37 in Table 2 have been assessed in terms of percentinhibition of p38-α activity in the presence of 15 μM concentration (SeeExample 7). The percent inhibition for all of these compounds ismeasurable, and is, for some compounds, as high as 100%.

The compounds in Table 3 contain modifications of the quinazolinenucleus as shown. These compounds have been prepared and tested fortheir ability to inhibit TGF-β and/or p38-α kinase. All of the compoundsin Table 3 are embodiments of formula (1) wherein Z³ is N and Z⁶ and Z⁷represent CH. In all cases the linker, L, is present and is NH.

TABLE 3 Compound No. Z⁵ Z⁸ Ar′ R³ 72 CH N 4-pyridyl 2-fluorophenyl 73 CHN 4-pyridyl 2-chlorophenyl 74 CH N 4-pyridyl phenyl 75 N N 4-pyridylphenyl 76 N CH 4-pyridyl phenyl

Additional compounds were prepared wherein ring A contains CR² at Z⁶ orZ⁷ where R² is not H. These compounds, which are all quinazolinederivatives, wherein L is NH and Ar′ is 4-pyridyl, are shown in Table 4.In Table 4, the percent inhibition was measured at 15 μM compound (or at1 μM compound as indicated). See Example 7. Inhibitions above 90% wereobserved.

TABLE 4 Compound No. R³ CR² as noted 77 2-chlorophenyl 6,7-dimethoxy 782-fluorophenyl 6-nitro 79 2-fluorophenyl 6-amino  80** 2-fluorophenyl7-amino  81** 2-fluorophenyl 6-(3-methoxybenzylamino)  82**2-fluorophenyl 6-(4-methoxybenzylamino) 83 2-fluorophenyl6-(2-isobutylamino) 84 2-fluorophenyl 6-(4-methylmercaptobenzylamino) 852-fluorophenyl 6-(4-methoxybenzoyl amino) 86 4-fluorophenyl 7-amino 874-fluorophenyl 7-(3-methoxybenzylamino) **Tested at 1 μM

EXAMPLE 7 Assay for p38 Kinase Inhibition

The compounds to be tested were solubilized in DMSO and diluted intowater to the desired concentrations. The p38 kinase was diluted to 10μg/ml into a buffer containing 20 mM MOPS, pH 7.0, 25 mM beta-glycerolphosphate, 2 mg/ml gelatin, 0.5 mM EGTA, and 4 mM DTT.

The reaction was carried out by mixing 20 μl test compound with 10 μl ofa substrate cocktail containing 500 μg/ml peptide substrate and 0.2 mMATP (+200 μCi/ml gamma-32P-ATP) in a 4× assay buffer. The reaction wasinitiated by the addition of 10 μl of p38 kinase. Final assay conditionswere 25 mM MOPS, pH 7.0, 26.25 mM beta-glycerol phosphate, 80 mM KCI, 22mM MgCl₂, 3 mM MgSO₄, 1 mg/ml gelatin, 0.625 mM EGTA, 1 mM DTT, 125μg/ml peptide substrate, 50 μM ATP, and 2.5 μg/ml enzyme. After a 40minute incubation at room temperature, the reaction was stopped by theaddition of 10 μl per reaction of 0.25 M phosphoric acid.

A portion of the reaction was spotted onto a disk of P81phosphocellulose paper, the filters were dried for 2 minutes and thenwashed 4× in 75 mM H₃PO₄. The filters were rinsed briefly in 95%ethanol, dried, then placed in scintillation vials with liquidscintillation cocktail.

Alternatively, the substrate is previously biotinylated and theresulting reactions are spotted on SAM^(2TM) streptavidin filter squares(Promega). The filters are washed 4× in 2M NaCl, 4× in 2M NaCl with 1%phosphoric acid, 2× in water, and briefly in 95% ethanol. The filtersquares are dried and placed in scintillation vials with liquidscintillation cocktail.

Counts incorporated are determined on a scintillation counter. Relativeenzyme activity is calculated by subtracting background counts (countsmeasured in the absence of enzyme) from each result, and comparing theresulting counts to those obtained in the absence of inhibitor.

IC₅₀ values were determined with curve-fitting plots available withcommon software packages. Approximate IC₅₀ values were calculated usingformula

IC ₅₀(app)=A×i/(1−A)

where A=fractional activity and i=total inhibitor concentration.

The compounds in Table 5 have IC₅₀ in the range of 0.1-1.5 μM vs p38-α:

TABLE 5 Compound No. Compound Name 162-phenyl-4-(4-pyridylmethylamino)-quinazoline  72-phenyl-4-(4-pyridylamino)-quinazoline  82-(4-fluorophenyl)-(4-pyridylamino)-quinazoline  12-(2-chlorophenyl)-(4-pyridylamino)-quinazoline 302-phenyl-4-(3-methoxyanilinyl)-quinazoline  52-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline  42-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline  32-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline 792-(2-fluorophenyl)-4-(4-pyridylamino)-6-amino quinazoline

Compounds 5 and 7 were tested for their specificity for p38 by assessingtheir ability to inhibit other kinases. These compounds were tested at50 μM and were soluble at 250 μM in 5% DMSO/95% water. The results areshown in Table 6.

TABLE 6 IC₅₀ (app) - μM DNA-dep Compound p38-γ JNK1 PKA PKC PK (PKD)cck2 EGF-R 5 227 167 >250 >100 120 245 4.2 7 >300 >300 310 >500 240 >50034

In Table 6, compound 5 is2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline and compound 7 is2-phenyl-4-(4-pyridylamino)-quinazoline.

As seen in Table 6, these compounds are highly specific for p38-α. Inaddition, these compounds were assessed with respect to p38-β and gavecurve fitted values of IC₅₀ as follows: Compound 5: 0.928 μM; Compound7: 3.65 μM.

What is claimed is:
 1. A compound of the formula

and the pharmaceutically acceptable salts thereof, wherein R¹ is H, alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, —SO₂NR₂, CN, CF₃, and NO₂, wherein each R is independently H or lower alkyl (1-4C); each R² is independently alkyl (1-6C), halo, OR, SR, OOCR, NROCR, COOR, RCO, CONR₂, SO₂NR₂, CN, CF₃ or NO₂, wherein each R is independently H or lower alkyl (1-4C); each of 1, m, and n is independently 0, 1 or 2; and Ar is phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, or benzimidazolyl, each optionally substituted with optionally substituted alkyl, alkenyl, alkynyl, aryl, N-aryl, NH-aroyl, halo, OR, NR₂, SR, —OOCR, —NROCR, RCO, —COOR, —CONR₂, SO₂NR₂, CN, CF₃, or NO₂, wherein each R is independently H or alkyl (1-4C); with the proviso that if l is 0, Ar must be optionally substituted 4-pyridyl, indolyl, 2- or 4-pyrimidyl, or benzimidazolyl.
 2. The compound of claim 1 wherein R² is halo, m is 0, and l is 1 or
 2. 3. The compound of claim 1 wherein Ar is 4-pyridyl.
 4. The compound of claim 1 wherein R¹ is H.
 5. The compound of claim 1 wherein R² is halo and l is 1 or 2 and m is 1 or
 2. 6. A compound selected from the group consisting of 2-phenyl-4-(4-pyridylamino)-quinazoline; 2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline; 2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(3-methoxyanilyl)-4-(4-pyridylamino)-quinazoline; 2-(2,6-dichlorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2,6-dibromophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2,6-difluorophenyl)-4-(4-pyridylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline; 2-(4-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-nitroquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino -6-aminoquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-7-aminoquinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(3-methoxybenzylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methoxybenzylamino)-quinazoline; 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(2-isobutylamino)-quinazoline; and 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methylmercaptobenzylamino)-quinazoline; and the pharmaceutically acceptable salts thereof. 